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21.
22.
Laura Kamp Gilberto Pasinelli Pietro Milanesi Sergei V. Drovetski Ziemowit Kosiski Serguei Kossenko Hugo Robles Manuel Schweizer 《Zoologica scripta》2019,48(1):17-32
Population divergence could be strongly affected by species’ ecology and might not be a direct response to climate‐driven environmental change. We tested this in the middle spotted woodpecker (Dendrocoptes medius), a non‐migratory, low‐dispersal habitat specialist associated with old deciduous forests of the Western Palearctic. We present the first phylogeographic study of this species integrating genetic data (three mitochondrial loci, one autosomal and one Z‐linked intron) with species distribution modelling. Based on this species’ ecology, we predicted that the middle spotted woodpecker could have colonized its current range from multiple Last Glacial Maximum (LGM) refugia and that strongly structured populations could be expected. Indeed, we discovered a strong genetic divergence between Asian and European populations, with a split estimated at around one million of years ago. This was surprising given only slight intraspecific variation in plumage and morphology. Although there was no significant phylogeographic structure within the Asian and European groups, we cannot exclude the possibility of multiple refugia within either group during the LGM. This has to be further investigated with more extensive geographic sampling and larger number of variable independently evolving markers. Future studies should also investigate potential differences in vocalizations and ecology between the two groups. Lineages showing similar level of genetic differentiation including woodpeckers are often treated as species‐level taxa. Comparison of our results with the phylogeographic history of other woodpeckers, suggests that sympatric species with similar life‐histories might have idiosyncratic phylogeographic patterns probably resulting from different ecological requirements or historic stochasticity. 相似文献
23.
Kohji Mori Shiho Gotoh Tomoko Yamashita Ryota Uozumi Yuya Kawabe Shinji Tagami Frits Kamp Brigitte Nuscher Dieter Edbauer Christian Haass Yoshitaka Nagai Manabu Ikeda 《The Journal of biological chemistry》2021,297(4)
GGGGCC (G4C2) repeat expansion in the C9orf72 gene has been shown to cause frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Dipeptide repeat proteins produced through repeat-associated non-AUG (RAN) translation are recognized as potential drivers for neurodegeneration. Therefore, selective inhibition of RAN translation could be a therapeutic avenue to treat these neurodegenerative diseases. It was previously known that the porphyrin TMPyP4 binds to G4C2 repeat RNA. However, the consequences of this interaction have not been well characterized. Here, we confirmed that TMPyP4 inhibits C9orf72 G4C2 repeat translation in cellular and in in vitro translation systems. An artificial insertion of an AUG codon failed to cancel the translation inhibition, suggesting that TMPyP4 acts downstream of non-AUG translation initiation. Polysome profiling assays also revealed polysome retention on G4C2 repeat RNA, along with inhibition of translation, indicating that elongating ribosomes stall on G4C2 repeat RNA. Urea-resistant interaction between G4C2 repeat RNA and TMPyP4 likely contributes to this ribosome stalling and thus to selective inhibition of RAN translation. Taken together, our data reveal a novel mode of action of TMPyP4 as an inhibitor of G4C2 repeat translation elongation. 相似文献
24.
Cecilia PC Soh Alastair SR Donald James Feeney Walter TJ Morgan Winifred M Watkins 《Glycoconjugate journal》1989,6(3):319-332
The tetrasaccharides GalNAcß1-4[NeuAc2-3]Galß1-4Glc and GalNAcß1-4[NeuAc2-3]Galß1-4GlcNAc were synthesised by enzymic transfer of GalNAc from UDP-GalNAc to 3-sialyllactose (NeuAc2-3Galß1-4Glc) and 3-sialyl-N-acetyllactosamine (NeuAc2-3Galß1-4GlcNAc). The structures of the products were established by methylation and1H-500 MHz NMR spectroscopy. In Sda serological tests the product formed with 3-sialyl-N-acetyllactosamine was highly active whereas that formed with 3-sialyllactose had only weak activity. 相似文献
25.
E Middlekoop E E Van der Hoek E M Bevers P Comfurius A J Slotboom J A Op den Kamp B H Lubin R F Zwaal B Roelofsen 《Biochimica et biophysica acta》1989,981(1):151-160
Crosslinking of membrane skeletal proteins such as spectrin by oxidation of their SH-groups can be provoked by treatment of intact erythrocytes with diamide. Shortly after exposure of human erythrocytes to diamide and despite the transverse destabilization of the lipid bilayer that was observed in these cells (Franck, P.F.H., Op den Kamp, J.A.F., Roelofsen, B. and Van Deenen, L.L.M. (1986) Biochim. Biophys. Acta 857, 127-130), no abnormalities could be detected regarding the asymmetric distribution of the phospholipids when probed by either the prothrombinase assay or brief exposure of the cells to a modified phospholipase A2 with enhanced membrane penetrating capacity. This asymmetry appeared to undergo dramatic changes however, when the ATP content of the cytosol had decreased to less than 10% of its original level during prolonged incubation of the treated cells. These observations indicate that the initial maintenance of phospholipid asymmetry in diamide-treated erythrocytes can be solely ascribed to the action of the ATP-dependent aminophospholipid translocase. This view is supported by experiments involving radiolabeled phospholipids of which trace amounts had been inserted into the outer membrane leaflet of diamide-treated red cells and which still showed a preferential translocation of both aminophospholipids in favour of the inner monolayer, be it that the efficiency of the translocase was found to be impaired when compared to control cells. 相似文献
26.
Transmissible spongiform encephalopathies, or prion diseases, are caused by misfolding and aggregation of the prion protein PrP. These diseases can be hereditary in humans and four of the many disease-associated missense mutants of PrP are in the hydrophobic core: V180I, F198S, V203I and V210I. The T183A mutation is related to the hydrophobic core mutants as it is close to the hydrophobic core and known to cause instability. We used extensive molecular dynamics simulations of these five PrP mutants to compare their dynamics and conformations to those of the wild type PrP. The simulations highlight the changes that occur upon introduction of mutations and help to rationalize experimental findings. Changes can occur around the mutation site, but they can also be propagated over long distances. In particular, the F198S and T183A mutations lead to increased flexibility in parts of the structure that are normally stable, and the short β-sheet moves away from the rest of the protein. Mutations V180I, V210I and, to a lesser extent, V203I cause changes similar to those observed upon lowering the pH, which has been linked to misfolding. Early misfolding is observed in one V180I simulation. Overall, mutations in the hydrophobic core have a significant effect on the dynamics and stability of PrP, including the propensity to misfold, which helps to explain their role in the development of familial prion diseases. 相似文献
27.
Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide‐repeat protein deposition 下载免费PDF全文
Kohji Mori Yoshihiro Nihei Thomas Arzberger Qihui Zhou Ian R Mackenzie Andreas Hermann Frank Hanisch Frits Kamp Brigitte Nuscher Denise Orozco Dieter Edbauer Christian Haass 《EMBO reports》2016,17(9):1314-1325
Intronic hexanucleotide (G4C2) repeat expansions in C9orf72 are genetically associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The repeat RNA accumulates within RNA foci but is also translated into disease characterizing dipeptide repeat proteins (DPR). Repeat‐dependent toxicity may affect nuclear import. hnRNPA3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G4C2 repeat RNA. We now report that a reduction of nuclear hnRNPA3 leads to an increase of the repeat RNA as well as DPR production and deposition in primary neurons and a novel tissue culture model that reproduces features of the C9orf72 pathology. In fibroblasts derived from patients carrying extended C9orf72 repeats, nuclear RNA foci accumulated upon reduction of hnRNPA3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hnRNPA3. Reduced nuclear hnRNPA3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci. 相似文献
28.
Brian P. Delisle Heather A. S. Underkofler Brooke M. Moungey Jessica K. Slind Jennifer A. Kilby Jabe M. Best Jason D. Foell Ravi C. Balijepalli Timothy J. Kamp Craig T. January 《The Journal of biological chemistry》2009,284(5):2844-2853
The pro-arrhythmic Long QT syndrome (LQT) is linked to 10 different genes
(LQT1–10). Approximately 40% of genotype-positive LQT patients
have LQT2, which is characterized by mutations in the human ether-a-go-go
related gene (hERG). hERG encodes the voltage-gated
K+ channel α-subunits that form the pore of the rapidly
activating delayed rectifier K+ current in the heart. The purpose
of this study was to elucidate the mechanisms that regulate the intracellular
transport or trafficking of hERG, because trafficking is impaired for about
90% of LQT2 missense mutations. Protein trafficking is regulated by small
GTPases. To identify the small GTPases that are critical for hERG trafficking,
we coexpressed hERG and dominant negative (DN) GTPase mutations in HEK293
cells. The GTPases Sar1 and ARF1 regulate the endoplasmic reticulum (ER)
export of proteins in COPII and COPI vesicles, respectively. Expression of DN
Sar1 inhibited the Golgi processing of hERG, decreased hERG current
(IhERG) by 85% (n ≥ 8 cells per group, *, p
< 0.01), and reduced the plasmalemmal staining of hERG. The coexpression of
DN ARF1 had relatively small effects on hERG trafficking. Surprisingly, the
coexpression of DN Rab11B, which regulates the endosomal recycling, inhibited
the Golgi processing of hERG, decreased IhERG by 79% (n
≥ 8 cells per group; *, p < 0.01), and reduced the plasmalemmal
staining of hERG. These data suggest that hERG undergoes ER export in COPII
vesicles and endosomal recycling prior to being processed in the Golgi. We
conclude that hERG trafficking involves a pathway between the ER and endosomal
compartments that influences expression in the plasmalemma.The human KCNH2 or ether-a-go-go related gene
(hERG)3
encodes the voltage-gated K+ channel α-subunits that
oligomerize to form the pore of the rapidly activating delayed rectifier
K+ current (IKr) in cardiac myocytes
(1–3).
Hundreds of hERG mutations are linked to the congenital
pro-arrhythmic Type 2 Long QT syndrome (LQT2) and functional studies suggest
that these mutations result in a loss of normal hERG K+ channel
(hERG) function (4,
5). In LQT2, missense mutations
are the dominant abnormality and many LQT2 missense mutations reduce hERG
K+ current (IhERG) by decreasing the intracellular
transport or trafficking of hERG to the Golgi apparatus (Golgi) and the cell
surface membrane (plasmalemma)
(6). Therefore, disruption of
hERG K+ channel trafficking appears to be a principal mechanism for
disease.Movement of proteins between membrane-bound intracellular compartments is
mediated by small transport vesicles, which bud from a donor compartment to
fuse with an appropriate acceptor compartment. The trafficking of many
transmembrane and secretory proteins between the ER and Golgi compartments is
dependent on the small GTPases ADP-ribosylation factor 1 (ARF1) and Sar1,
which regulate the formation of coat-associated protein complex I (COPI) and
II (COPII) vesicles, respectively
(7–19).
These small GTPases facilitate the polymerization of transport vesicle protein
coats on the donor membrane. Vesicular cargo selection, docking, and fusion to
the target membrane are regulated by adaptor proteins, SNARE proteins, and Rab
GTPases. To rationally develop novel therapeutic targets that may increase the
expression of trafficking-deficient LQT2 mutant channels, the molecular
mechanisms that regulate the trafficking of hERG need to be explored. The
purpose of this study is to identify transport proteins that regulate the
trafficking of wild type (WT) hERG. We used a strategy of testing specific WT
GTPases or ones containing dominant negative (DN) mutations to interfere with
their function. 相似文献
29.
30.
G Kamp 《Biological chemistry Hoppe-Seyler》1989,370(6):565-573
1) Glycogen is degraded in the abdominal muscle of the shrimp Crangon crangon (Decapoda, Crustacea) during the recovery period following work. The regulation of post-exercise glycogen breakdown and the properties of glycogen phosphorylase (EC 2.4.1.1) have been studied: 2) Glycogen phosphorylase exists as unphosphorylated b-form and phosphorylated a-form, the latter contains 1 molecule phosphate/subunit. Both forms of phosphorylase are dimers, isoenzymes have not been detected. 3) The purified b-form is inactive in absence of AMP and has very low affinities for AMP and Pi. For half-maximum activation 0.33 +/- 0.04 mM AMP is necessary, and the Km-value for Pi at 1 mM AMP is 48 +/- 5 mM. IMP does not affect the activity of the b-form. 4) The a-form is active without effectors, its Km-value for Pi is 5.3 +/- 1.5 mM. The proportion of phosphorylase a increases in vivo, from about 25% at rest, to approximately 90% upon work and remains at this high level during the first minutes of recovery. 5) It is concluded that the glycogenolytic flux in the abdominal muscle of the shrimp even during post-exercise periods depends on the level of the a-form the activity of which is restricted in time and extent by the cytoplasmic Pi concentration (Kamp, G. & Juretschke, H. P. (1987) Biochim. Biophys. Acta 929, 121-127). 相似文献